Because patients with Type 1 diabetes produce no insulin, the primary treatment for Type 1 diabetes is daily intensive insulin therapy. The treatment of Type 2 diabetes typically starts with management of diet and exercise. Although helpful in the short-run, treatment through diet and exercise alone is not an effective long-term solution for the vast majority of patients with Type 2 diabetes. When diet and exercise are no longer sufficient, treatment commences with various non-insulin oral medications. These oral medications act by increasing the amount of insulin produced by the pancreas, by increasing the sensitivity of insulin-sensitive cells, by reducing the glucose output of the liver or by some combination of these mechanisms. These treatments are limited in their ability to manage the disease effectively and generally have significant side effects, such as weight gain and hypertension. Because of the limitations of non-insulin treatments, many patients with Type 2 diabetes deteriorate over time and eventually require insulin therapy to support their metabolism. As their insulin resistance progresses, higher and higher doses of insulin are required to lower glucose levels. Concentrated insulin up to U-500 (500 units per ml) is commercially available for these patients, but it is limited to basal use due to a slow absorption profile.
Insulin therapy has been used for more than 80 years to treat diabetes. This therapy usually involves administering several injections of insulin each day. These injections consist of administering a long-acting basal injection one or two times per day and an injection of a fast-acting insulin at meal-time. Although this treatment regimen is accepted as effective, it has limitations. First, patients generally dislike injecting themselves with insulin due to the inconvenience and pain of needles. As a result, patients tend not to comply adequately with the prescribed treatment regimens and are often improperly medicated.
More importantly, even when properly administered, insulin injections do not replicate the natural time-action profile of insulin. In particular, the natural spike of the first-phase insulin release in a person without diabetes results in blood insulin levels rising within several minutes of the entry into the blood of glucose from a meal. By contrast, injected insulin enters the blood slowly, with peak insulin levels occurring within 80 to 100 minutes following the injection of regular human insulin.
One of the key improvements in insulin treatments was the introduction in the 1990s of rapid-acting insulin analogs, such as HUMALOG® (insulin lispro), NOVOLOG® (insulin aspart) and APIDRA® (insulin glulisine). However, even with the rapid-acting insulin analogs, peak insulin levels typically occur within 50 to 70 minutes following the injection. Because the rapid-acting insulin analogs do not adequately mimic the first-phase insulin release, diabetics using insulin therapy continue to have inadequate levels of insulin present at the initiation of a meal and too much insulin present between meals. This lag in insulin delivery can result in hyperglycemia early after meal onset. Furthermore, the excessive insulin between meals may result in an abnormally low level of blood glucose known as hypoglycemia. Hypoglycemia can result in loss of mental acuity, confusion, increased heart rate, hunger, sweating and faintness. At very low glucose levels, hypoglycemia can result in loss of consciousness, coma and even death. According to the American Diabetes Association, or ADA, insulin-using diabetic patients have on average 1.2 serious hypoglycemic events per year, many of which events require hospital emergency room visits by the patients.
The rapidity of insulin action is dependent on how quickly it is absorbed. When regular human insulin is injected subcutaneously at 100 IU/ml, the formulation is primarily composed of hexamers (approximately 36 kDa) which are not readily absorbed due to their size and charge. Located within the hexamer are two zinc atoms that stabilize the molecule. Post injection, a concentration driven dynamic equilibrium occurs in the subcutaneous tissue causing the hexamers to dissociate into dimers (about 12 kDa), then monomers (about 6 kDa). Historically, these regular human insulin formulations require approximately 120 min. to reach maximum plasma concentration levels.
Insulin formulations with a rapid onset of action, such as VIAject®, are described in U.S. Pat. No. 7,279,457, and U.S. Published Applications 2007/0235365, 2008/0085298, 2008/90753, and 2008/0096800, and Steiner, et al., Diabetologia, 51:1602-1606 (2008). The rapid acting insulin formulations were designed to create insulin formulations that provide an even more rapid pharmacokinetic profile than insulin analogs, thereby avoiding the patient becoming hyperglycemic in the first hour after injection and hypoglycemic two to four hours later. The rapid onset of VIAJECT® results from the inclusion of two key excipients, a zinc chelator such as disodium EDTA (EDTA) and/or calcium disodium EDTA which rapidly dissociates insulin hexamers into monomers and dimers and a dissolution/stabilization agent such as citric acid which stabilizes the dissociated monomers and dimers prior to being absorbed into the blood (Pohl et al, J. Diabetes Sci. and Technology, 2012. 6(4)755-763).
Unfortunately, early clinical trials with this product showed injection site discomfort. Inclusion of calcium, either as calcium chloride and/or the calcium salt of the EDTA, decreased injection site pain, supporting the theory that pain arose due to removal of calcium from the extracellular fluid in the injection site vicinity. However, the addition of calcium altered the pharmacokinetics.
It is an object of this invention to provide compositions of ultra-rapid acting injectable insulin compositions with reduced injection site discomfort. It is also an object of the present invention to provide specific concentrated insulin formulations for treating insulin resistant diabetic which modulate the pharmacokinetics and pharmacodynamics of injectable insulin compositions by increasing the rate of absorption from the site of subcutaneous injection.